Wednesday 10 May 2023

Low dose Clonazepam for MIA Autism, Ponstan and TRPM3 in Intellectual Disability, Clemastine to restore myelination in Pitt Hopkins, Improving Oxytocin therapy with Maca, Lamotrigine for some autism


Monty in Ginza, Tokyo

Today’s post comes from Tokyo and looks at 5 therapies already discussed in previous posts and follows up on recent coverage in the research. They all came up in recent conversations I have been having.

·      Low dose Clonazepam  – Maternal Immune Activation model of autism

·      Ponstan – TRPM3 causing intellectual disability  (ID/MR)

·      Clemastine – improving myelination in Pitt Hopkins syndrome model

·      Oxytocin – Maca supplement to boost effect

·      Lamotrigine (an anti-epilepsy drug) to moderate autism

The good news is that many of same therapies keep coming up.

Ponstan and TRPM3 caused ID/MR

There is a lot in this blog about improving cognition, which is how I called treating ID/MR.  There are very many causes of ID and some of them are treatable.

ID/MR was always a part of classic autism and in the new jargon is part of what they want to call profound autism.

I was recently sent a paper showing how the cheap pain reliever Ponstan blocks the TRMP3 channel and that this channel when mutated can lead to intellectual disability and epilepsy.

Mefenamic acid selectively inhibits TRPM3-mediated calcium entry.

My own research has established that mefenamic acid seems to improve speech and cognition, as well as sound sensitivity.  The latter effect I am putting down to its effect on potassium channels. 

De novo substitutions of TRPM3 cause intellectual disability and epilepsy

The developmental and epileptic encephalopathies (DEE) are a heterogeneous group of chronic encephalopathies frequently associated with rare de novo nonsynonymous coding variants in neuronally expressed genes. Here, we describe eight probands with a DEE phenotype comprising intellectual disability, epilepsy, and hypotonia. Exome trio analysis showed de novo variants in TRPM3, encoding a brain-expressed transient receptor potential channel, in each. Seven probands were identically heterozygous for a recurrent substitution, p.(Val837Met), in TRPM3’s S4–S5 linker region, a conserved domain proposed to undergo conformational change during gated channel opening. The eighth individual was heterozygous for a proline substitution, p.(Pro937Gln), at the boundary between TRPM3’s flexible pore-forming loop and an adjacent alpha-helix. General-population truncating variants and microdeletions occur throughout TRPM3, suggesting a pathomechanism other than simple haploinsufficiency. We conclude that de novo variants in TRPM3 are a cause of intellectual disability and epilepsy.


Fenamates as TRP channel blockers: mefenamic acid selectively blocks TRPM3

This study reveals that mefenamic acid selectively inhibits TRPM3-mediated calcium entry. This selectivity was further confirmed using insulin-secreting cells. KATP channel-dependent increases in cytosolic Ca2+ and insulin secretion were not blocked by mefenamic acid, but the selective stimulation of TRPM3-dependent Ca2+ entry and insulin secretion induced by pregnenolone sulphate were inhibited. However, the physiological regulator of TRPM3 in insulin-secreting cells remains to be elucidated, as well as the conditions under which the inhibition of TRPM3 can impair pancreatic β-cell function. Our results strongly suggest mefenamic acid is the most selective fenamate to interfere with TRPM3 function. 

Here, we examined the inhibitory effect of several available fenamates (DCDPC, flufenamic acid, mefenamic acid, meclofenamic acid, niflumic acid, S645648, tolfenamic acid) on the TRPM3 and TRPV4 channels using fluorescence-based FLIPR Ca2+ measurements. To further substantiate the selectivity, we tested the potencies of these fenamates on two other TRP channels from different subfamilies, TRPC6 and TRPM2. In addition, single-cell Ca2+ imaging, whole-cell voltage clamp and insulin secretion experiments revealed mefenamic acid as a selective blocker of TRPM3.



 Oxytocin does increase how emotional you feel; the difficulty is how to administer it in a way that provides a long lasting effect.  The half-life of oxytocin is a just minutes. The traditional method uses a nose spray.

I favour the use of a gut bacteria that stimulates the release of oxytocin in the brain.  The effect should be much longer lasting. Even then the effect is more cute than dramatic.

The supplement Maca does not itself produce oxytocin, but “it restores social recognition impairments by augmenting the oxytocinergic neuronal pathways”.

So Maca looks like an interesting potential add-on therapy to boost the effect of oxytocin.

One reader wrote to me with a positive report on using Maca by itself, without any oxytocin.


Oral Supplementation with Maca Improves Social Recognition Deficits in the Valproic Acid Animal Model of Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a congenital, lifelong neurodevelopmental disorder whose main symptom is impaired social communication and interaction. However, no drug can treat social deficits in patients with ASD, and treatments to alleviate social behavioral deficits are sorely needed. Here, we examined the effect of oral supplementation of maca (Lepidium meyenii) on social deficits of in utero-exposed valproic acid (VPA) mice, widely used as an ASD model. Although maca is widely consumed as a fertility enhancer and aphrodisiac, it possesses multiple beneficial activities. Additionally, it benefits learning and memory in experimental animal models. Therefore, the effect of maca supplementation on the social behavioral deficit of VPA mice was assessed using a social interaction test, a three-stage open field test, and a five-trial social memory test. The oral supplementation of maca attenuated social interaction behavior deficit and social memory impairment. The number of c-Fos-positive cells and the percentage of c-Fos-positive oxytocin neurons increased in supraoptic and paraventricular neurons of maca-treated VPA mice. These results reveal for the first time that maca is beneficial to social memory and that it restores social recognition impairments by augmenting the oxytocinergic neuronal pathways, which play an essential role in diverse social behaviors.

Maca (Lepidium meyenii) belongs to the cruciferous family and grows at high altitudes in Peru. In 2002, it was transplanted from Peru to the Yunnan Province of China. It is rich in dietary fiber; has many essential amino acids and nutrients including vitamin C, copper, and iron; and its root contains bioactive compounds. It is globally consumed and is popularly used as a fertility enhancer and aphrodisiac. On the other hand, with its potential to possess multi-nutritious components, it is reported to have diverse functions, including immunomodulation, antioxidant, antidepressant, antirheumatic, UV radiation protection, hepatoprotective, anti-fatigue, and neuroprotective effects. Interestingly, although the mechanism of the neuronal effect of maca is unclear, the uptake of maca extract improves learning and memory in memory-impaired model mice induced by either ethanol, ovariectomy, or scopolamine. However, the effects of maca on social memory impairment in neurodevelopmental disorders, including ASD, have not yet been tested.

In this study, the effects of maca on ASD animal models, in utero VPA-exposed mice, were investigated. The effect on social recognition by maca uptake with gavage was assessed using the social interaction test, a three-stage open field test, and the five-trail social recognition test. We also explored whether maca intake affects oxytocinergic signaling pathways, which play an important role in various social behaviors.

In this study, we showed that maca uptake rescues the deficits of social behavior and social recognition memory in VPA mice, a mouse model of autism. The c-Fos immunoreactivity of oxytocinergic neurons in SON and PVN increased significantly after maca treatment in VPA mice. Following previous studies indicating that OT administration ameliorates the impairment of social behavior in VPA mice, maca may also have improving effects on the deficit of social behavior and social recognition memory of VPA mice, probably by activating the OT neuronal pathway. Previous studies showed that maca could improve cognitive function in the mice model of impaired cognitive memory induced by either ovariectomy, ethanol, or scopolamine. Further studies are necessary to elucidate the potential link between maca and OT and to determine which components are involved in improving social recognition memory.

We have shown that maca improves the impairment of social memory and social behavioral deficits through oxytocinergic system modulation in this study. Although maca may not have an immediate effect on social behavioral deficits and takes days or weeks to demonstrate the effects, behavioral improvements, were visible regardless of the time of oral intake. The time between the very last oral intake of maca and the start of the social behavioral experiments in this study was more than 16 h. The duration of the maca’s effect on social behavioral deficits after the supplementation period is being investigated in our follow-up experiments. The possibility of the persistent effect of maca is very appealing, given that OT does not have a sustained effect due to its rapid metabolism, despite its immediate effects. Therefore, taking maca as a supplement while also receiving repeated OT treatment may have a synergistic, sustainable effect on improving social impairment in patients with ASD. Maca is already being used as a dietary supplement worldwide and has a high potential for practical applications.


This study showed for the first time that maca supplementation improves the impairment of social recognition memory in ASD model mice. We added the mechanism that social memory improvement may occur through the upregulation of oxytocinergic pathways. Maca highlights the possibility of treating social deficits sustainably in individuals with ASDs.


Low dose clonazepam

Professor Catterall was the brains behind low dose clonazepam for mice, I just translated it across to humans. It is one way to modify the E/I (excitatory/inhibitory) imbalance in autism.

I found that it gave a boost to cognition. Not as big as bumetanide, but worth having nonetheless.

I do not believe you have to be a bumetanide responder to respond well to low dose clonazepam.

Several people have written to me recently to say it works for their child.

Our reader Tanya is interested in the Maternal Immune Activation (MIA) trigger to autism. She highlighted a recent study showing how and why clonazepam can reverse autism in the MIA mouse model of autism. 

Clonazepam attenuates neurobehavioral abnormalities in offspring exposed to maternal immune activation by enhancing GABAergic neurotransmission

Ample evidence indicates that maternal immune activation (MIA) during gestation is linked to an increased risk for neurodevelopmental and psychiatric disorders, such as autism spectrum disorder (ASD), anxiety and depression, in offspring. However, the underlying mechanism for such a link remains largely elusive. Here, we performed RNA sequencing (RNA-seq) to examine the transcriptional profiles changes in mice in response to MIA and identified that the expression of Scn1a gene, encoding the pore-forming α-subunit of the brain voltage-gated sodium channel type-1 (NaV1.1) primarily in fast-spiking inhibitory interneurons, was significantly decreased in the medial prefrontal cortex (mPFC) of juvenile offspring after MIA. Moreover, diminished excitatory drive onto interneurons causes reduction of spontaneous gamma-aminobutyric acid (GABA)ergic neurotransmission in the mPFC of MIA offspring, leading to hyperactivity in this brain region. Remarkably, treatment with low-dose benzodiazepines clonazepam, an agonist of GABAA receptors, completely prevented the behavioral abnormalities, including stereotypies, social deficits, anxiety- and depression-like behavior, via increasing inhibitory neurotransmission as well as decreasing neural activity in the mPFC of MIA offspring. Our results demonstrate that decreased expression of NaV1.1 in the mPFC leads to abnormalities in maternal inflammation-related behaviors and provides a potential therapeutic strategy for the abnormal behavioral phenotypes observed in the offspring exposed to MIA.


Pitt Hopkins – Clemastine and Sobetirome

Poor myelination is a feature of much autism and is a known problem in Pitt Hopkins syndrome.

I did cover a paper a while back where the Pitt Hopkins researchers showed that genes involved in myelination are down-regulated not only in Pitt Hopkins, but in several other popular models of autism.

From the multiple sclerosis (MS) research we have assembled a long list of therapies to improve different processes involved in myelination. Today we can add to that list sobetirome (and the related Sob-AM2). Sobetirome shares some of its effects with thyroid hormone (TH), it is a thyroid hormone receptor isoform beta-1 (THRβ-1) liver-selective analog.

Some people do use thyroid hormones to treat autism, and indeed US psychiatrists have long used T3 to treat depression.

The problem with giving T3 or T4 hormones is that it has body-wide effects and if you give too much the thyroid gland will just produce less.

One proposed mechanism I wrote about long ago is central hypothyroidism, that is a lack of the active T3 hormone just within the brain. One possible cause proposed was that oxidative stress reduces the enzyme D2 that is used to convert circulating prohormone T4 to T3. The result is that your blood test says your thyoid function is great, but in your brain you lack T3.

It looks like using sobetirome you can spice up myelination in the brain, without causing any negative effects to your thyroid gland.

Rather surprisingly, sobetirome is already sold as a supplement, but it is not cheap like Clemastine, the other drug used in the successful study below.


Promyelinating drugs promote functional recovery in an autism spectrum disorder mouse model of Pitt–Hopkins syndrome

Pitt–Hopkins syndrome is an autism spectrum disorder caused by autosomal dominant mutations in the human transcription factor 4 gene (TCF4). One pathobiological process caused by murine Tcf4 mutation is a cell autonomous reduction in oligodendrocytes and myelination. In this study, we show that the promyelinating compounds, clemastine, sobetirome and Sob-AM2 are effective at restoring myelination defects in a Pitt–Hopkins syndrome mouse model. In vitro, clemastine treatment reduced excess oligodendrocyte precursor cells and normalized oligodendrocyte density. In vivo, 2-week intraperitoneal administration of clemastine also normalized oligodendrocyte precursor cell and oligodendrocyte density in the cortex of Tcf4 mutant mice and appeared to increase the number of axons undergoing myelination, as EM imaging of the corpus callosum showed a significant increase in the proportion of uncompacted myelin and an overall reduction in the g-ratio. Importantly, this treatment paradigm resulted in functional rescue by improving electrophysiology and behaviour. To confirm behavioural rescue was achieved via enhancing myelination, we show that treatment with the thyroid hormone receptor agonist sobetirome or its brain penetrating prodrug Sob-AM2, was also effective at normalizing oligodendrocyte precursor cell and oligodendrocyte densities and behaviour in the Pitt–Hopkins syndrome mouse model. Together, these results provide preclinical evidence that promyelinating therapies may be beneficial in Pitt–Hopkins syndrome and potentially other neurodevelopmental disorders characterized by dysmyelination.


Sobetirome  (also called GC-1)

Sobetirome is a thyroid hormone receptor isoform beta-1 (THRβ-1) liver-selective analog.

In humans, sobetirome lowers plasma LDL cholesterol and reduced plasma triglycerides, while its liver-selective activity helped avoid the side effects seen with many other thyromimetic agents.


Myelin repair stimulated by CNS-selective thyroid hormone action

Oligodendrocyte processes wrap axons to form neuroprotective myelin sheaths, and damage to myelin in disorders, such as multiple sclerosis (MS), leads to neurodegeneration and disability. There are currently no approved treatments for MS that stimulate myelin repair. During development, thyroid hormone (TH) promotes myelination through enhancing oligodendrocyte differentiation; however, TH itself is unsuitable as a remyelination therapy due to adverse systemic effects. This problem is overcome with selective TH agonists, sobetirome and a CNS-selective prodrug of sobetirome called Sob-AM2. We show here that TH and sobetirome stimulated remyelination in standard gliotoxin models of demyelination. We then utilized a genetic mouse model of demyelination and remyelination, in which we employed motor function tests, histology, and MRI to demonstrate that chronic treatment with sobetirome or Sob-AM2 leads to significant improvement in both clinical signs and remyelination. In contrast, chronic treatment with TH in this model inhibited the endogenous myelin repair and exacerbated disease. These results support the clinical investigation of selective CNS-penetrating TH agonists, but not TH, for myelin repair.


Compound protects myelin, nerve fibers


Research could be important in treating, preventing progression of multiple sclerosis, other neurodegenerative diseases

A compound appears to protect nerve fibers and the fatty sheath, called myelin, that covers nerve cells in the brain and spinal cord. The new research in a mouse model advances earlier work to develop the compound - known as sobetirome - that has already showed promise in stimulating the repair of myelin.

Lead author Priya Chaudhary, M.D., assistant professor of neurology in the OHSU School of Medicine who is focused on developing therapies for neurodegenerative diseases, said that the technique is a common step in drug discovery.

"It is important to show the effectiveness of potential drugs in a model that is most commonly used for developing new therapies," Chaudhary said.

The researchers discovered that they were able to prevent damage to myelin and nerve fibers from occurring, by stimulating a protective response in the cells that make and maintain myelin. They also reduced the activity of migroglia, a type of inflammatory cell in the brain and spinal cord that's involved in causing damage in multiple sclerosis and other diseases.

"The effects are impressive and are at least in part consistent with a neuroprotective effect with particular inhibition of myelin and axon degeneration, and oligodendrocyte loss," the authors write.

The discovery, if proven in clinical trials involving people, could be especially useful for people who are diagnosed with multiple sclerosis early in the disease's progression.

"The drug could protect the nervous system from damage and reduce the severity of the disease," Bourdette said.


Does Lamotrigine have the potential to 'cure' Autism?

Recently headlines appeared like this one:-

Scientists 'CURE autism' in mice using $3 epilepsy drug

It referred to the use of the epilepsy drug Lamotrigine to treat a mouse model of autism, caused by reduced expression of the gene MYT1L.

What the tabloid journalists failed to notice was that there has already been a human trial of Lamotrigine in autism.  That trial was viewed as unsuccessful by the clinicians, although the parents did not agree.

There were many comments in the media from parents whose child already takes this drug for their epilepsy and they saw no reduction in autism. There were some who found it made autism worse.


MYT1L haploinsufficiency in human neurons and mice causes autism-associated phenotypes that can be reversed by genetic and pharmacologic intervention


Lamotrigine therapy for autistic disorder: a randomized, double-blind, placebo-controlled trial

In autism, glutamate may be increased or its receptors up-regulated as part of an excitotoxic process that damages neural networks and subsequently contributes to behavioral and cognitive deficits seen in the disorder. This was a double-blind, placebo-controlled, parallel group study of lamotrigine, an agent that modulates glutamate release. Twenty-eight children (27 boys) ages 3 to 11 years (M = 5.8) with a primary diagnosis of autistic disorder received either placebo or lamotrigine twice daily. In children on lamotrigine, the drug was titrated upward over 8 weeks to reach a mean maintenance dose of 5.0 mg/kg per day. This dose was then maintained for 4 weeks. Following maintenance evaluations, the drug was tapered down over 2 weeks. The trial ended with a 4-week drug-free period. Outcome measures included improvements in severity and behavioral features of autistic disorder (stereotypies, lethargy, irritability, hyperactivity, emotional reciprocity, sharing pleasures) and improvements in language and communication, socialization, and daily living skills noted after 12 weeks (the end of a 4-week maintenance phase). We did not find any significant differences in improvements between lamotrigine or placebo groups on the Autism Behavior Checklist, the Aberrant Behavior Checklist, the Vineland Adaptive Behavior scales, the PL-ADOS, or the CARS. Parent rating scales showed marked improvements, presumably due to expectations of benefits.

One reader of this blog who heard all about the news and was sceptical, since after all it is a mouse model. Her 8 year old non-verbal child was not happy taking the drug Keppra and was already scheduled to try Lamotrigine. 

Within a week his teacher called to say he was saying his ABCs, the next week he was counting out loud, the following month he’s attempting to repeat words of interest and this week he’s spelling animals by memory, dolphin, duck, wolf, chicken, pig, etc.

We are 2 months in and at 50mg, our target dose is 100mg bid. Obviously with our success, I’ve been working with his doctor and will continue to.”



Even though every day new autism research is published, there is so much already in this blog that not much appearing is totally new to regular readers.

We saw several years ago that low dose clonazepam should be beneficial to some people with autism, in particular Dravet syndrome. Today we learnt a little more about why Nav1.1 might be disturbed beyond those with Dravet syndrome. In the maternal immune activation model it seems to be a winner. It seems to benefit many of those who have trialed it.

Treating myelination deficits has been well covered in this blog. In previous posts we saw how Pitt Hopkins syndrome researchers showed how myelination gene expression was disturbed in a wide range of autisms. Today we saw evidence to support such therapy and we discovered a new drug.

Oxytocin does help some people with autism, but not as much as you might expect. Today we learnt of a potential add on therapy, a supplement called Maca.

The idea that anti-epilepsy drugs might help some autism has been well covered. From low dose valproate to low dose phenytoin from Dr Philip Bird in Australia.

Treatment of Autism with low-dose Phenytoin, yet another AED

Recent research suggested that Lamotrigine should help some with autism and today you learned that it really does help in one case. The fact that a tiny study a few years ago suggested no responders just tells us that only a small subgroup are likely to benefit.

We already know that some people's autism is made worse by their epilepsy therapy. This is just what you would expect. Time to find a different epilepsy therapy.

My favorite new therapy, low dose mefenemic acid / ponstan has numerous effects. One reader without autism, but with an unusual visual dysfunction (visual snow syndrome) and a sound sensitivity problem contacted me a while to see if NKCC1 might be the root of his problem. I suggested he try Ponstan, which did actually work for him and is easy to buy where he lives. Now he sends me research into all its possible modes of action. One mode of action relates to a cause of intellectual disability (ID/MR). Is this a factor in why Ponstan seems to improve speech and cognition in some autism? I really don't mind why it works - I just got lucky again, that is how I look at it. The more I read the luckier I seem to get.


  1. Hi Peter, Though I am following your blog for some time, this is the first time that I am commenting. I tried Bumetanide for two weeks for my son at 0.5 mg dosage but it caused so much rage. After increasing the potassium dosage to 1000mg per day the rage decreased a bit but still it is unbearable. Do you think he is a candidate who is loosing too much potassium on Bumetanide? He is also on hydroxyzine from a few months. Do you know if there are any interactions betwen these two? Thanks a lot.

    1. Hello, sorry I didn't translate, I was in a hurry, hydroxyzine created extreme anger in my son, the sleep was very good, after a week of administration the seizures were extreme, I'm not a doctor but I think it increases or decreases serotonin in the brain. As a suggestion methylene blue, propranolol helps with aggression. We still see some very good things from lamictal and although we have been on 25 mg for a few days, after administration he has a few hours in which he is very happy, calm and wants to talk more, we are slowly increasing to 2 weeks, I'll keep you updated.

    2. Buga dragos, Thank you so much.. after I read your comment I stopped hydroxyzine and indeed his rage is gone. Thanks a lot for your suggestion

    3. Hello, I'm glad you listened to my advice, I was doing well with lamictal but a rash appeared on my face and I stopped, it's quite dangerous, we're on zoloft 50 mg a day, clonidine 0.75 2 times a day, it's more calm and wants to socialize more, let's hope that the zoloft won't cause hypomania....we have to go on vacation this summer.....

  2. There is a moderate interaction at the start of dual therapy.

    Some people are allergic to sulfonamide drugs, of which bumetanide is one. Some common antibiotics are also in this class. This might be the problem you are experiencing.

  3. Peter, how would one go about determining if their kid's autism is likely the MIA "type"?

    1. If the mother was quite ill during pregnancy that would activate her immune system.

  4. how much the dose of ponstan you recommend for autism kid Peter ?

    1. It looks like 250mg once a day in older kids to adults works well. In younger kids it would be prudent to scale the dose down based on weight.

      Some people may get GI side effects, but at this low dose nobody has yet reported any.

  5. I can’t tell you how invaluable this post is. Sometimes we read a post or article from you with all of your in-depth research and decide that it’s not quite right for our kids, or that our kid is already on a similar drug.

    Restating your research with parents anecdote sometimes is the push we need to double down and try again with something new.

    Thank you for all of your hard work!!

  6. My adult ASD son has a mutation in another trpm gene - his is trpm2. Any suggestions on substances that might influence that gene (we're not sure if it's a gain of function or loss of function mutation)? We've tried mito supps which were suggested by the doctor, but all we got was a more irritated kid. He misses the cutoff for ID/MR by only a few points and suffers from constant anxiety which we've never had success addressing.

    1. Fenamates are class of pain reliever. They block each TRPM channel to a different degree.

      When it comes to your channel TRPM2, DCPC is most potent, then meclofenamic acid, then tolfenamic acid, then flufenamic acid and mefenamic acid is the weakest.

      Many fenamates are available as drugs, but some are not widely used due to GI side effects. They are not so common in the US.

      You would have to balance potency with tolerance. Ponstan is the weakest but looks like the best tolerated - not a bad one to start with.

      In most cases, ion channel dysfunctions need you to block the channel rather than activate it. That does not mean you may not be an exception.

  7. Hello, Peter, thanks for your post. There are some open questions on Clemastine topic for me. First of all it’s a dose to get a certain effect. Research demonstrates about 10 mg per kg / day. One tablet is 1.34 mg, meaning it is approx. 0.08 mg per kg a day for a two years old kid. If more - side effects will not give a chance to progress in learning skills.. in other words we don’t want to get, at least, very sleepy kids. Second question is how to avoid side effects of antihistamine on immune system receptors in a long-term treatment? And third is a thought of any modern approaches in Multiple Sclerosis as most of them should have a promyelination impact. Also previous results in research showed a connection in synaptogenesis and RIMBP2 protein for PTHS ,at the end, it should be a complimentary medication to help with generation of functional synapses. Challenge is how to get a synergy effect.


    1. Natalia, I would start with the allergy dose of Clemastine, given in the evening, rather than a huge dose.

      In multiple sclerosis the existing myelin and oligodendrocytes get attacked in an inflammatory process, this is not happening in Pitt Hopkins, so not all MS therapy is going to be relevant.

      NAG (N-acetylglucosamine) is interesting and it is an OTC supplement.

      ALA is interesting and other modes of action may also benefit Pitt Hopkins.

      A PDE4 inhibitor such as Ibudilast (Japan only) or Daxas might also be beneficial.

  8. Hi Peter, I've been reading about nodular lymphoid hyperplasia in austistic children and stumbled upon this. It appears they had the same problem with Rapamycin I had but instead of stopping they added azithromycin to the mix. Just thought I would share for those looking at using Rapamycin.

    Treatment with sirolimus (initial dose 2 mg/m2 aiming at levels of 4–12 ng/ml, with an optimal target of 9 ng/ml) was then initiated, leading to the gradual resolution of gastrointestinal symptoms and to the normalization of fecal calprotectin in one year (Table 1). Due to the occurrence of few episodes of respiratory infection, including one episode of pneumonia and the notion of a disturbed immunoglobulin efficacy despite normal levels in APDS patients (17), immunoglobulin substitution and azithromycin prophylaxis (10 mg/kg/day, 3 days/week) were started with prompt interruption of recurrent infections.


  9. Forgot the link to the above post.

  10. I thought this would be a good post as well. Food hypersensitivity and ASD. For ASD children with GI dysfunction, it would be a good idea to find an ASD Gastro Doc that treats lymphoid hyperplasia. Arthur Krigsman is probably the go too guy in the states.

    He noticed lymphonodular hyperplasia in ASD kids.

    Maybe due to food hypersensitivity.

    Furthermore, he will order biologics if the child has a GI issues.


  11. One of the Up-to-date theories on nodular lymphoid hyperplasia.

    A compromised mucosal barrier in sIgAD allows for abnormal passage of food antigens through the gut wall. In some patients, this may lead to the formation of autoreactive antibodies and autoimmune disease due to molecular mimicry between large food proteins, such as milk, and host antigens. One study showed the presence of antibodies against milk in patients with IgA deficiency correlated with an increased frequency of serum autoantibodies

    Autoimmunity issues from a 1981 study.

    Sort of reminds me of Ramaekers folic acid autoantibodies theory

    1. Furthermore, NKCC1 has been shown to affect mucus secretion In the intestinal tract.

    2. Peter weird question, do you think the body could create an autoantibody to nkcc1?


    3. Stephan, just about anything seems to be possible.

    4. I agree anything is possible. I've been trying to figure out what causes low Sec IgA and ran across this. I guess its a defense mechanism of candida. Using nkcc1 as a way around the body's defense.

    5. Hello, I actually know the answer to this. Our immunologist asked for several locations of gut biopsy to check where the Iga gets ‘stuck’. It exists in sufficient quantities in lower levels and just doesnt get transported to the surface properly.
      He thinks this is a cell energy problem because the protein is heavy and needs a lot od energy for transportation. So it comes down again to mitochondria.
      Also, he finds Parvo b19 active quite a lot and he thinks this is part of an elaborate circle game which makes this even worse.

    6. I know Peter has written about the Hedgehog pathway in another post. However, I feel it might be beneficial to mention it here. It appears the loss of this pathway in the GI tract causes a decrease in mucin-secreting goblet cells

      I guess increasing autophagy, would help with this. (Mtor inhibitors increase autophagy)


    7. After a very deep dive into the shh and many other things that popped up on the way I probably now know less than before :-). Can you elaborate what you think?

    8. Sure, the Sonic Hedgehog pathway plays an important role in mitochondrial and cell regeneration. For example, Shh pathway can help with ROS. If there is a dysfunctional cell line like mucin-secrting goblet cells you can utilize mtor inhibitors to cause autophagy to create new cells and get rid of the broken ones. Im not an immunologist but there is cross talk between shh and mtor.


    9. This article does a good job explaining autophagy, Shh, oxidative stress. It's about Liptor one of Peter's polypill drugs.

  12. This comment has been removed by the author.

  13. If anyone is interested in FMT research Dr. Adams is hosting a zoom meeting to discuss ASD and MTT. Here is the link.


    May 24 9 pm EST / 6 pm PST
    Join Zoom Meeting
    Phone one-tap:
    US: +16027530140,,82115594983# or +17209289299,,82115594983#
    Meeting URL:

    1. Fyi, the times got changed.

      May 30 7:30 pm EST/ 4:30 pm PST
      register at:

      June 6 9:00 pm EST/ 6:00 pm PST
      register at:

      June 9 2:00 pm EST/ 11:00 am PST
      register at:

  14. Hi Peter my son takes tegretol low dose carbozepine the mood has improved and there are no more tantrums do you think that with clonazepan I could get more or do they work the same way?

    1. Carbozepine does effect some sodium ion channels. Low dose clonazepam is affecting one specific channel called Nav1.1.

      I think it is worthwhile trying low dose clonazepam to see if you get an extra benefit. If you are lucky you can get the liquid version, which it seems you can dilute with water. The liquid version is based on propylene glycol.

  15. Hello Peter. I recently came across chatgpt from openai and it could provide a valuable tool in Autism treatment research. One can ask questions such as "explain the link between autism and brain inflammation", "give me some publications about fever effect in Autism" etc. When you want more info just say "more". The knowledge database is up to September 2021. In the near future one should be able to ask for the summary of a publication, or even better to combine data from pmc database. Michalis

    1. Yes, other readers are already asking Chat gpt very specific questions about individual genes or receptors.

      I wonder if it can access all the papers behind pay walls, where normally only the abstract is free.

      It does a very good job of explaining things is layman’s English. Almost all the questions I get asked could be directed to Chat gpt.

  16. Hi Peter,

    I saw your recent comment that you are going to write another post on NO. I hope you'll cover methylene blue again in the future, as it seems that it rather impressively treats a broad range of the dysfunctions in Autism including endothelial dysfunction. I know its tempting to look for a "silver bullet" but it really does seem to me that this substance should be highly effective in Autism and is cheap and widely available even in the painful countries like UK and Australia.

    1. Have you used it successfully to treat autism? If so, what has been the effect.

    2. Peter, we are currently trialing it. It's not easy to figure out an effective dose because its unchartered territory but we're starting low (currently 3-5mg/day). Very early days - and I am trying to be cautious about remembering that my son is still developing and it could just be normal development and not a result of the drug - but it seems to me that after treatment with MB his mood is more stable and he has far more spontaneous language attempts. A few days ago was the first time we had ever heard him put two words together with appropriate context in a request (in this case, asking mum to open a lolly packet).

  17. Hi Peter, do you have any thoughts on Cogitum (Acetylamino-succinic acid or also called N-acetyl aspartic acid)? i have tried it yet, but i keep hearing couple of positive stories from people i know who tried on their kids. Just browsing it and also asked chat GPT, which all looks safe and worthwhile to try. One article was talking about its contribution to myelination. Am i missing something? Have you tried it before? Timur

    1. You have a lot of n acetyl aspartate (NAA) in your brain. Apparently NAA does not readily cross the blood brain barrier, so taking NAA orally may not have much impact on the level of NAA in the brain.

      If it has a positive effect do let us know.

  18. Just for your reference Peter, Dr. Fyre uses Diamox, hydroxyzine, leucovorin, and a hand full of vitamins to treat mitochondrial dysfunction/Cerebral folate deficiency.


    1. Thanks Stephen. It’s very good info. Diamox for blood flow and hydroxizine for anxiety?


    2. Hydroxyzine has anticholinergic properties, which I don't think is good for children with some level of cognitive impairment. I asked Dr. F why would he prefer hydroxyzine over ruparadine - he had no explanation. I also have a feeling, that he prescribes hydroxyzine to ALL pediatric patients (know two other kids symptomatically different from my child - everybody got hydroxyzine). Just be careful.

    3. Anti muscarinics (anti-cholinergics) are not necessarily bad for Autism. In fact it can be helpful as it’s a target for many toxins including pesticides and fertilizers. In fact antimuscarinics help improving myelination . Months back I stopped using SSRI because of the anti-cholinergic scare which later turned out to be very helpful

    4. The mouse model is interesting, but I'm a bit missing DB Randomised controlled studies in humans done by others than UC. On the other hand, the number of studies elucidating the cognitive impairment associated with the long-term use of anticholinergic drugs convinces me not to take this concern lightly, especially with the small kids. Clemastine is on my to-try list. I won't be surprised if it works. However, it is difficult to confirm its safety in the long-term.

  19. Furthermore,

    He uses these 2 test too. One is to check for Folate antibodies

    The other is to test mitochondrial dysfunction

    Both are cash pay fyi.


  20. Saw a great talk by Georgia Ede last week at the PHC UK Conference and she mentioned this study from last year. I guess you may have seen it already Peter, but just in case you haven't:
    The Ketogenic Diet for Refractory Mental Illness: A Retrospective Analysis of 31 Inpatients, Dr Danan, Toulouse, France.
    (bipolar, schizo, depression, not autism)

    I don't know how familiar you are with Dr Ede's work Peter, but I highly recommend watching her talk if you can. Given your work I would hope the PHC would give you access to watch it if you ask them. I imagine you're aware of most of the content already, but perhaps there are 1 or 2 nuggets of wisdom in there that are new to you.


  21. Hi Peter

    As always, love your blog. Gives me hope. Wondering about maca - would you be worried giving it to a 10 year old boy? I read that it is a phyto estrogen.
    Also, the article says they used Black maca - do you know any reputable brand?

    Best regards, Kirstine

    1. Kirstine, maca has been used for thousands of years in Peru and it is widely claimed to be a super food these days. People give it to babies upwards.

      I have not used it, so I cannot recommend a brand.

      Since the benefit suggested relates to oxytocin, I can point out that one reader started giving intranasal oxytocin recently and the unexpected effect was that it halted stereotypy/stimming.

      It has many other effects beyond on oxytocin.

  22. Hello! Long-time reader. I'm interested in helping my 14 year old autistic son. I was ill during my pregnancy as I have autoimmune illnesses( I was not yet diagnosed), as well as having had PANDAS since I was a child. My pregnancy was nightmarish. I'm struggling with how to help him. His memory is terrible, speech is difficult for him, social skills not great, lots of stims etc. I believe I had maternal immune activation, but what can I do now to help him? Thanks in advance.

    1. Maternal immune activation or maternal stress may well be a part of many people's autism. Mouse models can only ever be a guide because most autism is multifactorial.

      It does make sense to look at drugs that helped models of this type of autism.

      If your son also has autoimmune illnesses then he is likely to respond well to targeting them in treatment. Sometimes this can be gamechanging. One example is Humira, for some people.

      More broadly all the usual therapies are worth a trial. NAC should be tried. Low dose clonazepam now has evidence for MIA autism. But I would also try bumetanide and Ponstan. If your doctor will prescribe L type calcium channel blockers, I would try verapamil and amlodopine.

    2. Test for folate autoantibodies, especially if your thinking it's autoimmune.

  23. Paxmedica on news - "Collaboration Will Investigate a Next Generation Orally Delivered Anti-Purinergic Compound (Emodin)"

    Peter, any comments!?

    1. Janu, I wish them well.

      You can already target P2X7 with clemastine.

      They may produce an ultra expensive version of an existing OTC supplement. This us what happened with another supplement I wrote about.

    2. Hello Peter,
      My child has a genetic mutation which, besides some other mechanisms, causes myelin degeneration. I'm very interested in MS drugs, and Clemastine in particular. But, as you mentioned earlier, it has a strong anticholinergic effect - this is my big concern when choosing a right drug to prevent demyelination. You also mentioned that Monty was taking it for about three years, if I'm not mistaken. Didn't you feel Clemastine's negative impact on memory? Is there any other promyelinating drug I could try with a very young child that does not posses an anticholinergic effect? Thank you!

    3. Madina, myelination is a complex process. In MS there is proinflammatory signaling that leads to the microglia in the brain attacking the myelin and the oligodendrocytes that make the myelin. Then the process of remyelination is also down regulated due to too few oligodendrocytes and the ones that are there being "lazy".

      Your child does not have MS but likely shares some features. Not all the MS therapies may be appropriate.

      We had no trouble with a low dose of clemastine. I suggest half the allergy dose but all given in the evening.

      Other possible ideas include ALA and NAG (not NAC). There is ibudilast. There are several anti-inflammatory pro biotics that showed a benefit in MS - look it up on Google.

      Many antihistamines have anticholinergic effects. Many people seem unaffected.

  24. Hi Peter, the inflammation is there. NSE and S100 - the biomarkers of neuronal damage are continuesly elevated for the past two years. The child is on high ALA, and not so high NAC (only 600mg a day). He tolerates both, but there is no wow effect. He was on Ketotifen and rupatadin for months, but I don't think that the antihistamines of any generation have something to do with improving a neuroinflammation in our case.

    My son does not have MS, but, interestingly, he has some parkinsonian traits. The gait is severely affected, struggles with incontinence. He takes very long to process the information and respond (most people would think that he does not understand anything and cannot respond, and won't even bother communicating with him). On the other hand, he has a phenomenal memory. This makes me think that the areas of the brain affected are other than in AD. It is more about impaired neuronal firing, which is also could be due to loss of myelin. It is challenging to establish if genetic mutation is the only cause of neuro inflammation, and what should I target to reduce it. That's why my only strategy for now could be to rescue the remaining myelin and try to rebuild it. I just do not know the name of the enemy destroying it.

  25. Forgot to mention we never tried NAG, but may do. My husband was taking it for frozen shoulder. What dose is appropriate for a 3,5 y.o. (14 kg) child?
    Thank you!

    1. There is no particular dose yet for myelination repair in MS
      Use Google to look up the dose for 3 year olds with IBS, that would give you a starting point.

  26. any effect you see with clemastine Peter ?

    1. The effect of clemastine will take a few weeks or even longer so it clearly is subjective. The change I associate with clemastine was the development of independent opinions and the ability to say no. For example when asked whether a food item was wanted, the old answer was always yes, then it became sometimes "no thank you". So if you want a passive individual do not give clemastine.

      Clemastine also stabilizes the microglia, the immune cells in the brain. So the effect may not relate to myelin.

      Since many people with autism suffer from allergy clemastine looks a good choice since multiple benefits are possible.

  27. Peter, thanks for showing TRPM3. It looks like an excellent opportunity to target TRPM3, for those who did not see much from just using calcium channel blockers.

    However, the above paper indicates that Ponstan/Mefenamic acid has to reach a much higher plasma concentration than the current therapeutic doses used, to be able to inhibit TRPM3 effectively.

    It also presents the anti-convulsant drug Primidone as a viable option that works very well at current therapeutic doses.

  28. We got clonezapam mouth dissolving tablets , is it applicable for mcg doses by making it as suspension in water. Please advice.

    1. Yes, it should work. You need to shake well because it does not dissolve properly in water.

    2. Please correct me if I'm wrong , clonezapam dosage level for 12kg child.
      If the dosage is .0006mg/kg then it's 0.0072mg which is 1.44ml ?

    3. Assuming you put 0.5mg in 100 ml of water, the math looks good.

    4. What changes can one expect with low dose clonezapam. I'm trailing with it for 5 days now.. read post and comments saying effects can be seen after three days. He is hyperactive always running stimming plays with saliva.. everything got hyped. His cogni skills seems to be the same it's not lessened or increased. I'm worried that what if he is not responder.. should I give some more time to analyse.. please help..

    5. Only a subgroup of "autism" is going to respond to low dose clonazepam. The effective dose was shown in research to be in quite a narrow range and the absorption and excretion of a drug can vary between individuals and is affected by other drugs/supplements being taken. So someone may not show a cognitive gain because they are not in the responder subgroup, or because their dose is too high/low.

      If you use the tablet version in water as opposed to the liquid version that is made with propylene glycol you may not be giving an accurate/consistant dose. It is possible, but it is easy to get wrong. Some people get round this by using a compounding pharmacy.

  29. Is it .0006mg/kg per day or per dose if you do two doses a day? I have been doing that per day but breaking it up in 3 doses

    1. It is per day.
      Clonazepam has a long half life, so once a day in the morning should work fine.

  30. Hello Peter, I am planning on trialing Ponstan with my Son as he has profound autism with ID. Would 250 mg be too high for a 33kg 8 year old. I could only find 250 mg capsules. Also how long does it take to see results?
    I saw in few comments that you have stopped using NAC in polypill and instead use Postan now, is that correct? It's still not part of polypill though.

    1. Mandy, you can divide the capsule in half. Some are solid and can be split with a knife, others are in gelatin capsules that you can open and divide the contents in half.
      There are multiple effects, some are from the first dose and others take a few days.
      I have found that Ponstan does reduce the need for NAC in our case.
      I think you need to vary therapy over the years and so your personal Polypill should change over the years. Most people are interested in treating young children. My son is now an adult and I have not updated the details of his therapy. He has been taking Ponstan for a long time now. I did briefly trial it several years ago and saw no immediate effect back then. With the onset of extreme sound sensitivity the effect was obvious. I also think there are speech and cognitive benefits with continued use.

    2. Thanks for responding. I did give him 250mg last night. I will try half dose today.

    3. Mandy, I suggest you give it in the morning. You should see a greater effect that way.

    4. Remember to give Ponstan with food/fat, to protect the stomach.

  31. Hello Peter,
    We did trio WES testing and got the results today with nothing found. My son has profound intellectual disability as he is unable to sit and learn, he is yet to speak. He has gained and lost words on many occasions. We have trialed bumetanide and NAC, no changes noticed. Also multiple probiotics, supplements, TRS etc.
    Any suggestion on what to try next?

    1. Hello Mandy, what to do does depend on where you live.

      If you have done whole exome sequencing (WES) it is important to try and get the full results. Many labs, including the UK’s NHS, will only tell you if they have found a mutation on a gene that they have on their list for the condition that is being investigated, autism in your case.

      If you do WES on any human, you will find a list of mutated genes. It might be a list of 10 or 20, but it will not be zero. Sometimes these genes can be relevant, even if they are not strictly seen as autism genes. The list of autism genes is actually growing every year.

      You could go and see an autism doctor and see if he/she can find some effective therapies.

      There is a long list of therapies that do work for some people. Most do not have reliable diagnostic tests, but some do. Some have a test but people cannot access it, a good example is testing spinal fluid for cerebral folate deficiency, which could potentially be present in your son. There is a blood test ( ) but it looks like it is not sufficient.

      For some people antivirals (eg Valaciclovir) were key, for others antifungals (eg Fluconazole), or antibiotics (eg Rifaximin or Azithromycin) can be gamechangers.

  32. Hi Peter,
    Have you heard about this:
    I just got an email from the brain foundation about Cognilum which is a wearable device that is on track to get FDA approval in 2024. Sounds like it will be expensive but hopefully covered by insurance eventually. I was curious your thoughts around it. They have some you tube videos going over their clinical studies on their website.

    1. Hi Shana, I received the same email from the Brain Foundation. I have written about this kind of laser or LED therapy before. There are also other kinds of electrical or magnetic therapies. The key is for it to be home-based and not at a clinic. There is something similar in today's new post.


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